Difunctionalization Of Alkynes Research Articles

Iodine(III) Reagents in Radical Chemistry.

ConspectusThe chemistry of hypervalent iodine(III) compounds has gained great interest over the past 30 years. Hypervalent iodine(III) compounds show valuable ionic reactivity due to their high electrophilicity but also express radical reactivity as single electron oxidants for carbon and heteroatom radical generation. Looking at ionic chemistry, these iodine(III) reagents can act as electrophiles to efficiently construct C–CF3, X–CF3 (X = heteroatom), C–Rf (Rf = perfluoroalkyl), X–Rf, C–N3, C–CN, S–CN, and C–X bonds. In some cases, a Lewis or a Bronsted acid is necessary to increase their electrophilicity. In these transformations, the iodine(III) compounds react as formal “CF3+”, “Rf+”, “N3+”, “Ar+”, “CN+”, and “X+” equivalents. On the other hand, one electron reduction of the I(III) reagents opens the door to the radical world, which is the topic of this Account that focuses on radical reactivity of hypervalent iodine(III) compounds such as the Togni reagent, Zhdankin reagent, diaryliodonium salts, aryliodonium ylides, aryl(cyano)iodonium triflates, and aryl(perfluoroalkyl)iodonium triflates. Radical generation starting with I(III) reagents can also occur via thermal or light mediated homolysis of the weak hypervalent bond in such reagents. This reactivity can be used for alkane C–H functionalization. We will address important pioneering work in the area but will mainly focus on studies that have been conducted by our group over the last 5 years.We entered the field by investigating transition metal free single electron reduction of Togni type reagents using the readily available sodium 2,2,6,6-tetramethylpiperidine-1-oxyl salt (TEMPONa) as an organic one electron reductant for clean generation of the trifluoromethyl radical and perfluoroalkyl radicals. That valuable approach was later successfully also applied to the generation of azidyl and aryl radicals starting with the corresponding benziodoxole (Zhdankin reagent) and iodonium salts. In the presence of alkenes as radical acceptors, vicinal trifluoromethyl-, azido-, and arylaminoxylation products result via a sequence comprising radical addition to the alkene and subsequent TEMPO trapping. Electron-rich arenes also react with I(III) reagents via single electron transfer (SET) to give arene radical cations, which can then engage in arylation reactions. We also recognized that the isonitrile functionality in aryl isonitriles is a highly efficient perfluoroalkyl radical acceptor, and reaction of Rf-benziodoxoles (Togni type reagents) in the presence of a radical initiator provides various perfluoroalkylated N-heterocycles (indoles, phenanthridines, quinolines, etc.). We further found that aryliodonium ylides, previously used as carbene precursors in metal-mediated cyclopropanation reactions, react via SET reduction with TEMPONa to the corresponding aryl radicals. As a drawback of all these transformations, we realized that only one ligand of the iodine(III) reagent gets transferred to the substrate. To further increase atom-economy of such conversions, we identified cyano or perfluoroalkyl iodonium triflate salts as valuable reagents for stereoselective vicinal alkyne difunctionalization, where two ligands from the I(III) reagent are sequentially transferred to an alkyne acceptor.Finally, we will discuss alkynyl-benziodoxoles as radical acceptors for alkynylation reactions. Similar reactivity was found for the Zhdankin reagent that has been successfully applied to azidation of C-radicals, and also cyanation is possible with a cyano I(III) reagent. To summarize, this Account focuses on the design, development, mechanistic understanding, and synthetic application of hypervalent iodine(III) reagents in radical chemistry.

Generation of β-Halo Vinylsulfones through a Multicomponent Reaction with Insertion of Sulfur Dioxide.

A four-component reaction of terminal alkynes, aryldiazonium tetrafluoroborates, sulfur dioxide surrogate of DABCO⋅(SO2 )2 , and potassium halide in the presence of copper(I) chloride (10 mol %) gives rise to β-halo vinylsulfones with good stereoselectivity. The vicinal difunctionalization of alkynes through sulfonylation and halogenation with the insertion of sulfur dioxide works efficiently. A plausible mechanism is proposed, which includes a radical process.

Synthesis of (E)-β-iodovinyl sulfones via DTBP/I2 promoted difunctionalization of alkynes with sodium benzenesulfinates

GRAPHICAL ABSTRACT

Regioselective synthesis of difluoroalkyl/perfluoroalkyl enones via Pd-catalyzed four-component carbonylative coupling reactions.

The first example of Pd-catalyzed four-component carbonylative difluoroalkylation/perfluoroalkylation through the alkyne difunctionalization process is achieved. The reaction proceeds smoothly under mild conditions in the presence of 1 atm of CO at room temperature with good yields and E-selectivities. The utilization of CsF as an additive is vital to the success of the reaction.

Copper Nitrate Mediated Regio- and Stereoselective Difunctionalization of Alkynes: A Direct Approach to α-Chloro-β-nitroolefins.

An efficient copper nitrate mediated chloronitration reaction was developed for the direct synthesis of α-chloro-β-nitroolefins with high regio- and stereoselectivity from simple alkynes and low toxic stannous chloride. This protocol provides a direct access to polysubstituted alkenes with operational simplicity, good functional group tolerance, and a wide substrate scope. Various applications of given products allowed the straightforward assembly of molecular complexity and indicated them as promising and valuable building blocks in organic synthesis.

Fine Design of Photoredox Systems for Catalytic Fluoromethylation of Carbon-Carbon Multiple Bonds.

Trifluoromethyl (CF3) and difluoromethyl (CF2H) groups are versatile structural motifs, especially in the fields of pharmaceuticals and agrochemicals. Thus, the development of new protocols for tri- and difluoromethylation of various skeletons has become a vital subject to be studied in the field of synthetic organic chemistry. For the past decades, a variety of fluoromethylating reagents have been developed. In particular, bench-stable and easy-to-use electrophilic fluoromethylating reagents such as the Umemoto, Yagupolskii-Umemoto, Togni, and Hu reagents serve as excellent fluoromethyl sources for ionic and carbenoid reactions. Importantly, the action of catalysis has become a promising strategy for developing new fluoromethylations. For the past several years, photoredox catalysis has emerged as a useful tool for radical reactions through visible-light-induced single-electron-transfer (SET) processes. Commonly used photocatalysts such as [Ru(bpy)3](2+) and fac-[Ir(ppy)3] (bpy = 2,2'-bipyridine; ppy = 2-pyridylphenyl) have potential as one-electron reductants strong enough to reduce those fluoromethylating reagents, resulting in facile generation of the corresponding fluoromethyl radicals. Therefore, if we can design proper reaction systems, efficient and selective radical fluoromethylation would proceed without any sacrificial redox agents, i.e., via a redox-neutral process under mild reaction conditions: irradiation with visible light, including sunlight, below room temperature. It should be noted that examples of catalytic fluoromethylation of compounds with carbon-carbon multiple bonds have been limited until recent years. In this Account, we will focus on our recent research on photoredox-catalyzed fluoromethylation of carbon-carbon multiple bonds. First, choices of the photocatalyst and the fluoromethylating reagent and the basic concept involving a redox-neutral oxidative quenching cycle are explained. Then photocatalytic trifluoromethylation of olefins is discussed mainly. Trifluoromethylative difunctionalization reactions, i.e., simultaneous introduction of the CF3 group and a different functional group across carbon-carbon double bonds, are in the middle of the discussion. Oxy-, amino-, and ketotrifluoromethylation allow us to synthesize various organofluorine compounds bearing C(sp(3))-CF3 bonds. In addition, the synthesis of valuable trifluoromethylated alkenes is also viable when the olefins have an appropriate leaving group or undergo deprotonation. The present reaction system features high functional group compatibility and high regioselectivity. Furthermore, future prospects, especially trifluoromethylative difunctionalization of alkynes and difluoromethylation of alkenes, are also discussed.

ChemInform Abstract: Alkyne Difunctionalization by Dual Gold/Photoredox Catalysis.

AbstractA selective tandem nucleophilic addition/cross‐coupling reaction of alkynes using visible‐light‐promoted dual gold/photoredox catalysis is developed.

Visible-Light-Initiated Na2-Eosin Y Catalyzed Highly Regio- and Stereoselective Difunctionalization of Alkynes with Alkyl Bromides.

A highly regioselective and stereoselective addition of alkyl bromides (amino-brominated aromatic β,β-dicyanoalkenes) to arylacetylenes by photoredox catalysis was developed. This difunctionalization of arylacetylenes was accomplished under ambient and metal-free conditions to produce alkenyl bromides in high efficiency with a wide range of group tolerance.

Tetrabutylammonium Iodide Mediated Synthesis of β-Alkoxy Sulfides and Vinyl Sulfones by Using Benzenesulfonyl Chlorides as the Sulfur Sources under Acidic or Alkaline Conditions

The tetrabutylammonium iodide (TBAI)-promoted generation of sulfur-containing compounds from benzenesulfonyl chlorides and alkenes is described. Under acidic condition, a wide range of β-alkoxy sulfides were obtained in good to excellent yields, whereas under alkaline conditions, various vinyl sulfones were produced in moderate to good yields. A novel preparation of (<i>E</i>)-β-iodovinyl sulfones was achieved through direct difunctionalization of alkynes with benzenesulfonyl chlorides and TBAI.

Gold catalysis with less fuss

In an advance that simplifies gold redox catalysis, a research team led by A. Stephen K. Hashmi of Heidelberg University, in Germany, has discovered a means for carrying out visible-light-mediated reactions without the need for an auxiliary oxidant or a ruthenium or iridium photosensitizer. The additional reagents are typically needed to promote oxidation of gold(I) to gold(III) as part of the catalytic cycle. The Hashmi group determined that a phosphine gold(I) chloride catalyst can function as its own photosensitizer when irradiated with visible light. When paired with an aryldiazonium salt, the gold(I) species is oxidized to a gold(III) species that can complete the difunctionalization of alkynes to make α-aryl ketones (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201511487). What’s more, by using a P,N-bidentate ligand, the researchers were able to isolate and obtain the X-ray crystal structure of the gold(III) species (shown above). Chemists have debated whether gold(III) intermediates are involved

Photosensitizer-Free Visible-Light-Mediated Gold-Catalyzed 1,2-Difunctionalization of Alkynes.

Under visible-light irradiation, the gold-catalyzed intermolecular difunctionalization of alkynes with aryl diazonium salts in methanol affords a variety of α-aryl ketones in moderate to good yields. In contrast to previous reports on gold-catalyzed reactions that involve redox cycles, no external oxidants or photosensitizers are required. The reaction proceeds smoothly under mild reaction conditions and shows broad functional-group tolerance. Further applications of this method demonstrate the general applicability of the arylation of a vinyl gold intermediate instead of the commonly used protodemetalation step. This step provides facile access to functionalized products in one-pot processes. With a P,N-bidentate ligand, a stable aryl gold(III) species was obtained, which constitutes the first direct experimental evidence for the commonly postulated direct oxidative addition of an aryl diazonium salt to a pyridine phosphine gold(I) complex.

Alkyne Difunctionalization by Dual Gold/Photoredox Catalysis.

Highly selective tandem nucleophilic addition/cross-coupling reactions of alkynes have been developed using visible-light-promoted dual gold/photoredox catalysis. The simultaneous oxidation of Au(I) and coordination of the coupling partner by photo-generated aryl radicals, and the use of catalytically inactive gold precatalysts allows for high levels of selectivity for the cross-coupled products without competing hydrofunctionalization or homocoupling. As demonstrated in representative arylative Meyer-Schuster and hydration reactions, this work expands the scope of dual gold/photoredox catalysis to the largest class of substrates for gold catalysts and benefits from the mild and environmentally attractive nature of visible-light activation.

Direct vicinal difunctionalization of alkynes through trifluoromethylation and aminosulfonylation via insertion of sulfur dioxide under catalyst-free conditions

Direct vicinal difunctionalization of alkynes through a catalyst-free four-component reaction of Togni's reagent, alkynes, sulfur dioxide, and hydrazines at room temperature is developed, which generates (E)-3,3,3-trifluoroprop-1-ene-1-sulfonohydrazides in good yields.

ChemInform Abstract: The Copper‐Catalyzed Synthesis of β‐Trifluoromethylated Acrylonitriles and Trifluoromethyl‐Substituted 2H‐Azirines

Abstractusing a novel alkyne difunctionalization reaction

Palladium-Catalyzed Intermolecular Aryldifluoroalkylation of Alkynes.

A palladium-catalyzed aryldifluoroalkylation of alkynes with ethyl difluoroiodoacetate and arylboronic acids as reaction partners is described. The alkyne difunctionalization process provides various aryldifluoroalkylated products in one pot under mild reaction conditions. A wide range of alkynes and diverse arylboronic acids are compatible with these reaction conditions. High reaction efficiency and broad substrate scope are the notable features of this transformation. Preliminary mechanistic investigations indicate that a difluoroalkyl radical addition pathway is involved in this transformation.

ChemInform Abstract: β‐Ketophosphonate Formation via Aerobic Oxyphosphorylation of Alkynes or Alkynyl Carboxylic Acids with H‐Phosphonates.

A synergistic Cu/Fe-catalyzed aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonate is disclosed. The useful β-ketophosphonate products were obtained in good yields under oxygen atmosphere in a novel way. This reaction exhibits a wide substrate scope, and the mechanistic experiments indicate that a radical mechanism forms both C–P and C═O bonds simultaneously. This mechanism contrasts existing aerobic difunctionalization of alkynes.

ChemInform Abstract: Direct Vicinal Difunctionalization of Alkynes: An Efficient Approach Towards the Synthesis of Highly Functionalized Fluorinated Alkenes

AbstractReview: [92 refs.

ChemInform Abstract: Direct Difunctionalization of Alkynes with Sulfinic Acids and Molecular Iodine: A Simple and Convenient Approach to (E)‐β‐Iodovinyl Sulfones.

AbstractA wide range of the title compounds (III) is efficiently obtained from simple and easily available starting materials with excellent stereo‐ and regioselectivity and without use of any metal catalyst or additives.

Metal-Free Difunctionalization of Alkynes with 2-Chlorodithiane for Synthesis of β-Ketodithianes.

Dithianes are versatile umpolung intermediates in organic synthesis but have rarely been employed in radical cross-coupling reactions. Here we describe the oxidative coupling method for alkyne difunctionalization under metal-catalyst-free conditions. The efficient protocol directly affords a variety of β-ketodithianes in good to excellent yields with high regioselectivities. It provides a general pathway for accessing valuable dithianes with controlled formation of a new C-C bond and a C-O bond via a radical coupling pathway.

β-ketophosphonate formation via aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonates.

A synergistic Cu/Fe-catalyzed aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonate is disclosed. The useful β-ketophosphonate products were obtained in good yields under oxygen atmosphere in a novel way. This reaction exhibits a wide substrate scope, and the mechanistic experiments indicate that a radical mechanism forms both C-P and C═O bonds simultaneously. This mechanism contrasts existing aerobic difunctionalization of alkynes.